genetic risk factors for multi-system inflammatory syndrome in children and pediatric post covid condition

Conditions: COVID-19; Post-Acute COVID-19; Post-Acute COVID19 Syndrome; Multi-System Inflammatory Syndrome in Children; Pediatric Inflammatory Multisystem Syndrome; Post COVID-19 Condition; Post-COVID-19 Syndrome

Summary: we will perform whole exome sequencing on dna from saliva. we will include: children with a history of mis-c; children with post-covid condition; and controls in order to identify rare, high impact genetic variants in immunological genes and pathways in children with a history of mis-c or pediatric post-covid condition.

rationale: following infection with sars-cov-2, some children develop the potentially life-threatening disease multi-system inflammatory syndrome in children (mis-c) and some children develop post-covid condition (formerly 'long covid'). it is unknown why some children develop severe or prolonged symptoms after sars-cov-2 infection, while most children have asymptomatic or mild disease. we hypothesize that rare variants in genes associated with the immune system predispose children to develop mis-c or post-covid condition after infection with sars-cov-2. objective: primary objective: to identify rare, high impact genetic variants in immunological genes and pathways in children with a history of mis-c or pediatric post-covid condition. secondary objectives: to analyze the clinical characteristics and long-term effects of pediatric covid-19 and mis-c. to characterize the functional and clinical impact of genetic variants in mis-c and post-covid condition and identify targets for therapy. study design: we will do an observational study. we will perform whole exome sequencing (wes) using next generation sequencing (ngs) on dna from blood or saliva. we will include: (1) mis-c cases: children with a history of mis-c; (2) post-covid condition cases: children with post-covid condition; and (3) controls: sars-cov-2 exposed age-matched control group: children who were infected with sars-cov-2 but did not develop moderate to severe covid-19, mis-c or post-covid condition. study population: children 0-19 years old with a history of mis-c (n=100), post-covid condition (n=100), or uncomplicated sars-cov-2 infection (n=200). main study parameters/endpoints: 1. to evaluate if some children with mis-c or post-covid condition have an inborn error of immunity by determining the presence of pathogenic or likely pathogenic variants in immunological genes 2. to evaluate if a larger proportion of cases with mis-c or post-covid condition have rare and presumably deleterious variants in immunological genes than children with an asymptomatic or mild infection

Eligibility criteria:
inclusion criteria: 1. children (\<19 years) with a history of mis-c: as defined according to who criteria. 2. children (\<19 years) with post-covid condition: as defined according to the who case definition. this includes a history of probable or confirmed prior sars-cov-2 infection, with signs and symptoms (including fatigue, shortness of breath, cognitive dysfunction) that are present after 12 weeks, last at least 2 months, have an impact on daily functioning and are not explained by an alternative diagnosis. 3. 'exposed' control group: children (\<19 years of age): a history of proven sars-cov-2 infection (rt-pcr, antigen test or serology positive). if the child has been vaccinated against sars-cov-2, the first documented infection must have been prior to the vaccination. exclusion criteria: 1. no informed consent 2. group 1 (mis-c): no specific exclusion criteria 3. group 2 (post-covid condition): other plausible cause of symptoms and/or a history compatible with chronic fatigue syndrome prior to infection with sars-cov-2. children with a history of mis-c who suffer prolonged signs and symptoms will be included in the mis-c group. 4. group 3 ('exposed' control group): mis-c or post-covid condition; and/or moderate or severe course of covid-19, as defined in the copp-study (n20.043) (need for supplemental oxygen and/or intensive care admission because of covid-19 and/or death) and/or first degree relative with long covid or mis-c.

Keywords: covid-19 post-covid condition mis-c pims-ts